The Pope is discussing birth control in light of the Zika outbreak, and another study published in the Lancet Infectious Diseases yesterday describes another case report in which the Zika virus genome was detected in the amniotic fluid of two pregnant women in the absence of other possible congenital infections. At a press briefing in Washington, D.C. last weekend, Christopher Dye, the Director of Strategy in the Office of the Director General at the World Health Organization, said they are “expecting hundreds and hundreds of thousands of Zika infections” and that “there are likely to be a lot more cases of microcephaly as well,” though they cannot be precise on the numbers. Several scientists are already convinced that Zika causes microcephaly, as I reported last week, but many others as well as public health agencies have refrained from confirming a causal link. Yet some of those same public health agencies are urging women to take precautions to avoid pregnancy or infection to reduce the risk of microcephaly.

Why the apparent mixed messages?

It’s reasonable to feel confused by what feels like conflicting information, but the epidemic of Zika provides an excellent case study on how science works and the tension that arises at the intersection between scientific consensus and public health action.

“I don’t think we have seen any evidence against a link; we just haven’t looked to disprove it,” Ian Mackay, a virologist and associate professor at the University of Queensland in Australia, told me. Mackay is among those scientists vocally urging others not to consider a link between Zika and microcephaly settled. “Rather we’ve extraordinarily eagerly followed the link and responded as if it were proven. A premature correlation, if wrong, could waste time, money and effort following up on a coincidence rather than keeping an open mind to find the cause(s).”

Too many past missteps have taught scientists not to jump to early conclusions about perceived connections. But gathering the amount of information and evidence required to achieve more certainty takes time—not just months but years.

“From the point of view of public health actions, we cannot wait for scientific certainty,” said Kenneth Camargo, Jr. MD, PhD, a senior associate professor at the Social Medicine Institute at Rio de Janeiro State University in Brazil, where the most Zika infections and the biggest spike in microcephaly cases have occurred. “There are significant signs of a possible association between the virus and microcephaly, which must be taken into account in health policy design at least until the connection is categorically dismissed,” said Camargo, also an associate editor at the American Journal of Public Health. That’s why we see a difference in perspectives between researchers and public health officers, he told me. “If you wait until you have a bullet proof case from the point of view of science, you may have waited too long to act on a potential public health crisis.”

The way this tension plays out was summarized nicely by Dye at the press briefing at the American Association for the Advancement of Science meeting last weekend: “What everybody would like us to do as public health officials is say, ‘Now we’ve proved it.’ It’s not going to be like that. What happens is that evidence mounts piece by piece. There are two case control studies in the Americas underway at the moment, and the results of those studies will be important. But if we take all of the information we have at the moment, the case for a causal link is becoming quite strong, and I think we’ve got to a point now where we have to consider that Zika is guilty unless proven innocent.”

Josiane da Silva holds her son Jose Elton, who was born with microcephaly, outside her house in Alcantil, Paraiba state, Brazil, Sunday, Feb. 7, 2016. (AP Photo/Felipe Dana)

That is the kind of information that led a journalist to ask Pope Francis on his return flight from Mexico about abortion and birth control during the Zika outbreak. The Pope reaffirmed the Catholic doctrine that abortion is an absolute evil but that "avoiding pregnancy is not an absolute evil. In certain cases, as in this one, such as the one I mentioned of Blessed Paul VI, it was clear." The mention of Pope Paul VI refers to that pope’s allowing nuns at risk for rape to use contraception. "I would also urge doctors to do their utmost to find vaccines against these two mosquitoes that carry this disease," Pope Francis went on to say. "This needs to be worked on."*

At the press briefing, Dye went on to explain why the WHO and other organizations must operate from that premise: “The point of doing that is not to say we believe [Zika] is the cause [of microcephaly]. The point is then to consider what the public health actions should be as a result of that, what precautions we should take. The evidence for the causal link is becoming stronger and stronger.”

So let’s review what that evidence is as though Zika really were on trial and what the holes in the case are.

Cases in which a fetus or infant with microcephaly is found to have a Zika infection have not found evidence of other infections, including dengue virus, chikungunya virus, Toxoplasma gondii, rubella, cytomegalovirus, herpes, HIV, Treponema pallidum and parvovirus B19.

A retrospective review of pregnant women infected with Zika during a French Polynesia outbreak showed 17 additional cases of neurological problems in fetuses or infants.

Although most microcephaly cases linked to Zika have occurred in women infected by the virus in their first trimester, later infections have been implicated as well, said Anthony Fauci of the U.S. National Institute of Allergy and Infectious Diseases at the press briefing. “Some documentation exists of women who actually got infected late in the pregnancy and there was some effect on the fetus,” Fauci said. “So the bottom line is that it’s likely the most profound effect is early on, but we don’t know enough about it to give a gradated risk as you go further on in the pregnancy.”

At the same time, as Dye said at the press briefing, “Microcephaly is not a novel clinical condition. Microcephaly has many causes and exists at low background rates in many populations. It’s the rise in microcephaly that we’ve been concerned with, and that rise is apparently associated with the spread of Zika infections.”

Mackay pointed out that a range of chemical and biological factors can contribute microcephaly, and that it’s certainly clear that not every Zika infection results in microcephaly.

“I do not think much more can be said about whether the presence of virus in the fetal brain causes microcephaly until we find a mechanism for Zika infection leading to disease and until we’ve examined all the other known causes and looked for unknown causes,” Mackay told me. “Instead of selective case reports, it would be informative to see the results of studies that examine these questions in a wider sample of the community, with and without a laboratory-confirmed Zika infection or microcephaly. Until we know more about cases versus a control population, we will be guessing.”

So here are the gaps in the case against Zika:

Most evidence has come from case reports, which provide biological plausibility but not the population-level epidemiological evidence necessary to strongly support the link.

The spike in microcephaly cases in Brazil is more complex than it first appears: a) cases were likely under-reported before the Zika outbreak occurred; b) more reporting could be a result of increased awareness, which leads to more identification; c) over-reporting could be occurring as a result of changes in the way microcephaly is defined; d) some cases could be false positives as a result of the changing diagnostic criteria; e) other unidentified factors could be contributing to an increase. That said, the increase in extreme microcephaly is clearly correlated in time with the arrival of the Zika virus.